When a child is diagnosed with cancer, one of the first questions the parents ask is “Will my other children get cancer?” A new study from Huntsman Cancer Institute (HCI) at the University of Utah suggests the answer to that question depends on whether a family history of cancer exists. The research results were published online in the International Journal of Cancer and will appear in the November 15 print issue.
The study, led by Joshua Schiffman, M.D., medical director of HCI’s High Risk Pediatric Cancer Clinic and a pediatric hematologist/oncologist in in the Department of Pediatrics at the University of Utah, examined the family medical history of 4,482 children diagnosed with cancer over a 43-year period to determine the cancer risk in their relatives.
The research team found that when children were diagnosed with any kind of cancer at age 18 or younger, the risk to their parents, siblings, or children for childhood cancer doubled compared to families with no childhood cancer patients. If the cancer diagnosis came when the child was age 4 or less, the risk to close relatives for childhood cancer increased almost four times.
“No one had previously studied the question, so we simply told parents there was no evidence of increased risk to the other children,” said Schiffman. “Now we can give an evidence-based answer — the risk depends on your family history of cancer.”
This is the first study that uses the Utah Population Database (UPDB) to broadly examine the risk of all types of cancer in relatives of children with cancer. This unique resource at the University of Utah links genealogies and cancer registry data from Utah to medical records and vital records, including Utah death certificates.
“Because our data came from the UPDB, the assessment of family history in our study does not rely on self- or family-reported medical history,” said lead author Karen Curtin, Ph.D., a genetic epidemiologist and UPDB assistant director. “Self-reporting of family medical history depends on an individual’s memory, while our data comes from the statewide Utah Cancer Registry that records nearly all cancer cases, which reduces possible errors in reporting family cancers.”
The team also assessed known inherited genetic syndromes in adult relatives of pediatric cancer patients. They found cancers associated with Li-Fraumeni Syndrome (LFS) seemed to be driving the increased risk to relatives in families with a history of cancer.
“Not all children’s cancers are hereditary,” said Schiffman. “But the numbers in this study suggest that the proportion of hereditary childhood cancers may be significantly higher than the 5-10% generally cited in adult hereditary cancers, and likely even more than 20%.
“LFS is one of the most devastating cancer syndromes,” said Schiffman. “It causes a variety of cancers in both children and adults. For people with LFS, the lifetime risk of getting cancer is 80% to 90%, but with increased and early screening for tumors, there’s early indication of a very high survival rate, perhaps even approaching100%. In a previous study, LFS patients who did not receive early screening only had a 20% survival rate.”
Although childhood cancer rarely occurs in the population, based on their findings, the authors recommended collection of three generations of family medical history for all newly diagnosed pediatric cancer patients and referral of families with a history of early-onset cancers in children or adults for genetic counseling. In addition, parents of children diagnosed with cancer before age five with a family history of cancer should be advised of the potential for increased risk to other children in the family.
“We want to encourage the taking of a family history as part of routine care. With all cancers, but perhaps especially with childhood cancers, so many other questions seem so urgent, a family history may not seem to be the most pressing issue,” said co-author Wendy Kohlmann, director of HCI’s Genetic Counseling Program. “When families are referred into genetic counseling, we can provide them with more information about the risks and actions they can take.”
“For families with previously unidentified LFS, following these recommendations could actually save the lives of multiple family members if at risk individuals are identified and early cancer surveillance programs implemented,” Schiffman said.
This article provides a historical overview of the online database (www.insight-group.org/mutations) maintained by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT). The focus is on the mismatch repair genes which are mutated in Lynch Syndrome. APC, MUTYH and other genes are also an important part of the database, but are not covered here. Over time, as the understanding of the genetics of Lynch Syndrome increased, databases were created to centralise and share the variants which were being detected in ever greater numbers. These databases were eventually merged into the InSiGHT database, a comprehensive repository of gene variant and disease phenotype information, serving as a starting point for important endeavours including variant interpretation, research, diagnostics and enhanced global collection. Pivotal to its success has been the collaborative spirit in which it has been developed, its association with the Human Variome Project, the appointment of a full time curator and its governance stemming from the well established organizational structure of InSiGHT.
The InSiGHT colorectal cancer hereditary mutation database can be found here
Don’t be embarrassed to go to your GP .
A consultant at West Middlesex University Hospital is urging people to go to their GP if they have symptoms linked to bowel cancer. Dr Kevin Monahan, Consultant Gastroenterologist, runs the Family History of Bowel Cancer Clinic at West Middlesex, and is speaking out to support bowel cancer awareness month during April. He says: “If for the last three weeks you’ve had blood in your poo or it’s been looser, go and see your GP. “We know that people are reluctant to visit their GP if they experience symptoms because they’re embarrassed and worried about wasting the doctor’s time. “But it could save your life. Over 90 per cent of bowel cancer patients diagnosed with the earliest stage of the disease survive five years from diagnosis compared with only 6.6 per cent of those diagnosed with advanced disease. “Bowel cancer is the third most common cancer in the UK for men and the second most common cancer for women. Every year more than 30,000 people will develop it. An estimated 13,000 people die annually from bowel cancer. “Many people worry about getting bowel cancer, sometimes because a relative has had it. At West Middlesex I run a Family History of Bowel Cancer Clinic specifically for those people who may be at higher risk of developing the disease. “The cause of most bowel cancers is not known, but we do know that some risk factors can increase your chances of developing cancer. This includes having one close relative aged under 50 or at least two close relatives on the same side of the family who developed bowel cancer at any age. “If these apply to your family and you’re worried about your risk of developing bowel cancer, you may want to talk to your GP. If your GP thinks there’s a chance you may have an increased risk of developing bowel cancer because of your family history, they can refer you to the Family History of Bowel Cancer Clinic here or elsewhere for advice and treatment.”
Making Universal Screening for a Reality: The Lynch Syndrome Screening Network
March 22nd, 2012 11:35 am ET – From CDC
Deb Duquette, MS, CGC, Sarah Mange, MPH- Michigan Department of Community Health, Cecelia Bellcross, PhD, MS- Emory University, Heather Hampel, MS, CGC- The Ohio State University, Kory Jasperson, MS, CGC- Huntsman Cancer Institute
Authors are all from the Lynch Syndrome Screening Network (LSSN) Founding Board of Directors
flow chart individualEvery day, about 400 people in the United States are diagnosed with colorectal cancerExternal Web Site Icon. Approximately twelve of them have Lynch syndrome, a hereditary condition that increases the risk of colorectal cancer and other cancers. Identifying people with Lynch syndrome could have substantial health benefits for them, their families, and communitiesExternal Web Site Icon.
Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancer; it also leads to increased risks of ovarian, pancreatic, and several other cancers, which often occur at a younger than average age. Lynch syndrome occurs among men and women in all ethnic groups in the United States. A diagnosis of Lynch syndrome offers an opportunity to 1) enhance cancer prevention and screening measures for patients and families, 2) prevent cancer or detect it earlier, and 3) save lives and is cost-effectiveExternal Web Site Icon.
In 2009, the Evaluation of Genomic Applications in Practice and Prevention Working Group published an evidence-based recommendationExternal Web Site Icon that every person newly diagnosed colorectal cancer should be offered screening for Lynch syndrome to identify opportunities to reduce morbidity and mortality in their relatives.
Lynch syndrome screening is performed by analyzing tissue from the person with colorectal cancer for specific pathologic features. If the results suggest the possibility of Lynch syndrome, the affected person is offered genetic counseling and additional testing. Offering screening to all newly diagnosed colorectal cancer patients—regardless of age, ethnicity or family history—is termed “universal screening.” This approach supports an objective of Healthy People 2020, which is to:
‘Increase the number of newly diagnosed colorectal cancer patients who are screened for Lynch syndromeExternal Web Site Icon’
In September 2011, a group of 37 dedicated people from leading cancer institutions created the Lynch Syndrome Screening Network (LSSN)External Web Site Icon, with the goal of reducing the cancer burden associated with Lynch syndrome. LSSN has already received more than 80 institutional applications for membership. More than half of the applicant institutions have already implemented universal Lynch syndrome screening and the others are either interested or in the process. The LSSN will facilitate implementation of universal Lynch syndrome screening by promoting sharing of resources, protocols, and data. LSSN Founding members have already gathered existing educational resources and created a new database to monitor progress toward achieving the Healthy People 2020 objective for Lynch syndrome.
Each first-degree relative (parent, sibling, or child) of a person with Lynch syndrome has a 50% risk of carrying the gene mutation and should be offered genetic counseling and testing. Relatives of a person with Lynch syndrome who are not found to have the gene mutation for Lynch syndrome will typically have the same risk for colorectal cancer as the general population, and their children will not be at risk for Lynch syndrome. Family members who are found to have the gene mutation for Lynch syndrome can be offered earlier and more frequent screening for colorectal and other cancers. Because these people can pass the gene mutation on to their children, the children should also be offered testing after reaching adulthood.
Genetic testing in family members of persons with a Lynch syndrome gene mutation is called “cascade testing.” Cascade testing will allow the Healthy People 2020 objective to achieve population health impact by preventing additional cancers in family members.
March is National Colorectal Cancer Awareness month. This month, increasing awareness of Lynch syndrome is especially timely, as the importance of collecting and sharing information regarding family history of colorectal cancer is being promoted throughout the United States (Colon Cancer AllianceExternal Web Site Icon ; Family PLZExternal Web Site Icon). People with an immediate family member diagnosed with colorectal cancer should share this information with their health care providers, so that screening for Lynch syndrome can be considered.
Lynch Syndrome International is promoting March 22, 2012, as LYNCH SYNDROME PUBLIC AWARENESS DAY. To learn more, please visit Lynch Syndrome International Home pageExternal Web Site Icon ( or the Lynch Syndrome Hereditary Cancers Public Awareness pageExternal Web Site Icon or LSI on FacebookExternal Web Site Icon)
A new study1 that combines genetic information on bowel cancer with NHS patient outcome data has found a link between family history of the disease and a better chance of survival, published in the British Journal of Cancer.
Cancer Research UK scientists, based at the University of Leeds, in collaboration with the National Cancer Intelligence Network (NCIN), matched the genetic data2 of nearly 11,000 bowel cancer patients with data from the National Cancer Data Repository (NCDR) on treatment and survival.
And by tracking the survival of these bowel cancer patients they found that the 1,700 people (16 per cent) with a family history of the disease were 11 per cent less likely to die from bowel cancer within 5 years of diagnosis than patients who had no family history of the disease3.
The scientists believe the better prognosis for those with a family history may be linked to the fact that these patients were more likely to have right-sided tumours, that are biologically different to other tumour types, which may respond better to treatment.
Dr Eva Morris, a Cancer Research UK funded scientist at the University of Leeds, and lead author of the research, said: “Our study has found a relationship between family history of bowel cancer and a higher chance of survival.
“Although we haven’t been able to determine exactly why this is the case, it does demonstrate how we can use data that we already routinely collect to help us develop a better understanding of bowel cancer and its genetic causes.
“As datasets such as the NCDR expand and collect more detailed information this opens up the possibility of using this data to help develop better targeted treatments for patients, based upon their individual genetics.”
Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “This is another important step forward in our understanding of bowel cancer. Now we need to find out more about what’s causing this difference. Studies like this, which link genetic data to detailed patient information, may help us develop a more personalised approach to treating cancer in the future.
“Survival from bowel cancer is best when it’s diagnosed and treated in the early stages, so anyone who notices possible symptoms of the disease – blood in stools, or changes to bowel habits lasting longer than three weeks should get this checked out. If you think you may have a family history of bowel cancer it’s worth discussing this with your GP.”
“Thank you for agreeing to complete our survey. It should take no more than 20 minutes to complete and we appreciate your input in helping Bowel Cancer UK to understand the issues affecting young people with bowel cancer.
Your answers are completely confidential.
If you have any concerns about bowel cancer, please do not hesitate to contact the Bowel Cancer UK Information and Support Service on 0800 8 40 35 40.”
In Lynch Syndrome, the risk of developing endometrial cancer ( is very high and equals or even exceeds the risk of colorectal cancer (CRC) in female gene carriers.49 The overall prognosis of patients diagnosed with EC is relatively good, with a 10-year survival of approximately 80%. However, 20% of the patients will ultimately die from the disease. Moreover, a substantial proportion of patients need treatment with radiation and/or chemotherapy.
The main goal of surveillance for EC is detection and treatment of premalignant lesions (ie, endometrial hyperplasia) or EC at an early stage and thereby improving the prognosis for the patients. The World Health Organization classifies endometrial hyperplasia as simple or complex determined by the degree of architectural abnormality, and as having or not having atypia. Nieminen et al50 studied serial specimens of normal endometrium, simple hyperplasia and complex hyperplasia with and without atypia during 10 years of surveillance. MMR deficiency was observed in 7% of normal endometrium, 40% of simple hyperplasia, 100% of complex hyperplasia without atypia and 92% of complex hyperplasia with atypia, suggesting that in LS, contrary to the traditional view, complex hyperplasia with and without atypia was equally important as precursor lesions of EC.
In 2011, Auranen and Joutsiniemi51 performed a systematic review of all studies that addressed gynaecological cancer surveillance in women who belonged to LS families. The authors identified five studies in the literature that included a total of 647 women.52–56 The screening methods applied in the studies varied from only transvaginal (or transabdominal) ultrasound (two studies) to a combination of transvaginal ultrasound and endometrial biopsy (two studies) and hysteroscopic endometrial biopsy (one study). The intervals between examinations varied between 1 year in three studies, 1–2 years in one study and 2–3 years in another study. In the studies that used only ultrasound as the screening tool, no EC were detected and only interval cancers occurred. However, in the studies with a protocol that also included endometrial biopsies, the detection of premalignant lesions and EC was improved.
Renkonen-Sinisalo et al54 compared the Federation of Gynecology and Obstetrics (FIGO) stages of the screen-detected cancers with those of EC diagnosed after presentation of signs or symptoms. Although less advanced cancers were observed in the screen-detected group, the difference was not statistically significant. The main advantage of the surveillance programme seems to be the identification of precursor lesions. No benefit was shown for ovarian cancer surveillance. Auranen and Joutsiniemi51 concluded that the available studies do not adequately allow for evidence-based clinical decisions.
Since that review, another retrospective study was published on the impact of gynaecological screening in MSH2 carriers (n=54).57 Nine women were diagnosed with EC, five of which were within 1 year of the previous negative screening test (transvaginal ultrasound and/or endometrial biopsy) and two were at initial screening. Of the nine EC, seven were localised cancers (stage I), and one was at an advanced stage (stage III). There were no deaths due to EC. Six women had ovarian cancer, three of which were within 1 year of a previous normal screening. Two died from ovarian cancer. The authors concluded that gynaecological screening did not result in earlier detection of gynaecological cancer.
In view of the uncertain effect of the surveillance programme, it is important to consider possible disadvantages of the programme. Elmasry et al58 assessed the patient acceptability of the available screening modalities. Transvaginal ultrasound was associated with less discomfort than hysteroscopy or Pipelle biopsy. There was no significant difference between the pain scores for hysteroscopy and Pipelle biopsy. Huang et al59 compared a new patient-centered approach by combining endometrial biopsies and colonoscopy under sedation. This approach was much more acceptable than an endometrial biopsy as a single procedure without sedation.
Wood et al60 evaluated the effect of gynaecological screening in LS families on psychological morbidity. The authors did not demonstrate any adverse psychological effect in the screened population, even in those with false positive screening results.
The value of surveillance for EC is still unknown. Surveillance of the endometrium by gynaecogical examination, transvaginal ultrasound and aspiration biopsy starting from the age of 35–40 years may lead to the detection of premalignant disease and early cancers (category of evidence III) and should be offered to mutation carriers (grade of recommendation C). The pros and cons should be discussed (table 5). Given the lack of evidence of any benefit, gynaecological surveillance should preferably be performed as part of a clinical trial.
Pros and cons of surveillance for gynaecological cancer
|Identification of precursor lesions of endometrial cancer||Small risk of death|
|Identification of early stage endometrial cancer (not proved)||Physical burden of surveillance examination especially Pipelle biopsy|
|No evidence of efficacy for early stage ovarian cancer detection|
Schmeler et al61 have shown in a retrospective study that prophylactic hysterectomy and oophorectomy is very effective in LS: none of the patients who underwent prophylactic surgery (61 out of 315) developed endometrial or ovarian cancer, whereas 33% of patients who did not have surgery developed EC and 5.5% developed ovarian cancer.
A recent study documented two cases of LS patients who developed primary peritoneal cancers after prophylactic surgery.62 A cost-effectiveness analysis of prophylactic surgery versus gynaecological screening showed that risk-reducing surgery was associated with both the lowest costs and highest number of quality-adjusted life years.63 ,64
In view of the very high risk of EC, the substantial proportion of women who will die from the disease, the morbidity associated with treatment and the effectiveness of prophylactic surgery, there is agreement that the option of prophylactic hysterectomy should be discussed with mutation carriers who have completed their family. However, there are still some important questions that should be addressed.
First, should prophylactic surgery include salpingo-oophorectomy? The risk of developing ovarian cancer in mutation carriers is approximately 9% with the highest risks in MLH1 and MSH2 mutation carriers and the lowest risk in MSH6 mutation carriers. Although the prognosis of unselected patients with ovarian cancer (and also of patients with ovarian cancer associated with BRCA1 and BRCA2 mutations) is very poor, recent studies suggested that the biology of ovarian cancer associated with LS may be different. Three studies showed that the majority of symptomatic ovarian cancers (77–81%) in LS are diagnosed at an early stage (FIGO stages I and II).65–67 In a multicentre study, Grindedal et al66 collected a large number (n=144) of prospectively diagnosed cases of ovarian cancer and demonstrated a very good prognosis with a 10-year survival of 81%.
Prophylactic surgery in postmenopausal women should include salpingo-oophorectomy. However, salpingo-oophorectomy in premenopausal women is associated with various adverse effects such as an immediate onset of menopause as a result of oestrogen deprivation potentially resulting in vasomotor symptoms and possible sexual dysfunction. Oestrogen deprivation may also lead to a higher risk of osteoporosis. A large study by Madalinska et al68 in 846 carriers of a BRCA1 and BRCA2 mutations reported significantly more endocrine symptoms in the patients who underwent prophylactic oophorectomy compared to women who underwent surveillance of the ovaries. No significant differences were observed in the level of sexual activities between the two groups, but women in the prophylactic surgery group reported significantly more discomfort (vaginal dryness and dyspareunia), less pleasure and less satisfaction during sexual activities. Despite this, the study did not reveal any other differences in quality of life. Usually, hormone replacement therapy is prescribed in premenopausal women after salpingo-oophorectomy, which may partly reduce the vasomotor symptoms but has no effect on sexual discomfort.
In view of the recent study that suggests a relatively good prognosis of ovarian cancer in LS, it is questionable whether the possible small gain in life expectancy outweighs the adverse effects of prophylactic salpingo-oophorectomy at a young age.
The second question is how these issues should be discussed with the patient and how the patient can be supported in their decision-making? The best approach is to inform the patient fully about all pros and cons of prophylactic surgery. As a basis for this discussion, the pros and cons are summarised in table 6. Depending on the type of information, a gynaecologist, geneticist, clinical psychologist or other specialists should be involved. Ideally, this information should also be available in written form.
Pros and cons of prophylactic hysterectomy with and without salpingo-oophorectomy
|Prevention of endometrial and ovarian cancer||Small risk of death|
|Prevention of morbidity related to treatment||Mortality surgery (0.1%)|
|Morbidity surgery (5–9%)|
|Pelvic surgery makes colonoscopy more difficult and painful and may reduce chance of full colonoscopy|
|Psychosocial problems (10–20%)|
|Early menopause depending of age at surgery|
|Sexual problems related to hysterectomy and early menopause|
|Probably very small risk of developing primary peritoneal carcinoma after oophorectomy|
The third question is from which age surgery should be recommended. The risk of endometrial and ovarian cancer increases from the age of 40 years. The optimal timing of prophylactic surgery, therefore, would be around the age of 40 years.
Hysterectomy and bilateral oophorectomy largely prevents the development of endometrial and ovarian cancer (category of evidence III) and is an option to be discussed with mutation carriers who have completed their families especially after the age of 40 years (grade of recommendation C). Also, if CRC surgery is scheduled, the option of prophylactic surgery at the same time should be considered. All pros and cons of prophylactic surgery should be discussed.
Yarnall, Crouch & Lewis (Division of Genetics and Molecular Medicine, King’s College London, United Kingdom.). Cancer Epidemiology 2013 Jan 29
Background: Epidemiological studies have identified potentially modifiable risks for colorectal cancer, including alcohol intake, diet and a sedentary lifestyle. Modelling these environmental factors alongside genetic risk is critical in obtaining accurate estimates of disease risk and improving our understanding of behavioural modifications. Methods: 14 independent single nucleotide polymorphisms identified though GWAS studies and reported on by the international consortium COGENT were used to model genetic disease risk at a population level. Six well validated environmental risks were selected for modelling together with the genetic risk factors (alcohol intake; smoking; exercise levels; BMI; fibre intake and consumption of red and processed meat). Through a simulation study using risk modelling software, we assessed the potential impact of behavioural modifications on disease risk. Results: Modelling the genetic data alone leads to 24% of the population being classified as reduced risk; 60% average risk; 10% elevated risk and 6% high risk for colorectal cancer. Adding alcohol consumption to the model reduced the elevated and high risk categories to 9% and 5% respectively. The simulation study suggests that a substantial proportion of individuals could reduce their disease risk profile by altering their behaviour, including reclassification of over 62% of heavy drinkers. Conclusion: Modelling lifestyle factors alongside genetic risk can provide useful strategies to select individuals for screening for colorectal cancer risk. Impact: Quantifying the impact of moderating behaviour, particularly related to alcohol intake and obesity levels, is beneficial for informing health campaigns and tailoring prevention strategies.
Over the last 30 years the lifetime risk of colorectal cancer (CRC) for men has almost doubled, from 3.5% to 6.9% in the UK in 2008. For women the increase is more than a quarter, rising from 3.9% to 5.4%. Since both genetic and environmental factors contribute to the susceptibility to colorectal cancer, this trend may be due to a change in the dietary and lifestyle factors of the general population leading to higher levels of obesity and more sedentary pastimes.
The major risk factor for colorectal cancer is age and over 85% of colorectal cancer occurs in people over the age of 60. Other risk factors include the presence of polyps and people having an Ashkenazi Jewish genetic heritage. The use of non-steroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy and aspirin use have also been associated with disease risk. However, it is estimated that between 52 and 57% of colorectal cancers are associated with lifestyle and environmental factors. Many risk factors for colorectal cancer may be modified by intervention, ranging from known risks, such as increased risk from a sedentary lifestyle and dietary changes. The evidence for dietary factors indicates possible increased risk from diets low in fibre, garlic, calcium, fruit, vegetables and fish and high in red and processed meat. In addition to alcohol, BMI, smoking and exercise, we chose to model the most consistent and well validated dietary findings, which suggest that low levels of fibre and high levels of red and processed meat are both significant risk factors.
The international consortium COGENT (COlorectal cancer GENeTics) have identified many of the known genetic variants that predispose to CRC with the 14 single nucleotide polymorphisms (SNPs) found to be convincingly associated with CRC risk from GWA studies summarized in Houlston et al.’s recent update. Of these 14 SNPs, the mean odds ratio per allele is 1.14, with the highest odds ratio reported for SNP rs16892766 near the EIF3H gene (OR 1.28).
The identification of SNPs that contribute to susceptibility for CRC has raised the prospect of genetic screening. Companies such as DeCODEme and 24andme include panels of SNPs for CRC in their genetic testing panels, yet research suggests that the genetic risk prediction alone is of questionable utility. In this research study, we combined the known genetic risk with data on the environmental risks for CRC, enabling more complete risk prediction. We applied a statistical risk model and to determine the impact of modelling environmental factors alongside the 14 genetic susceptibility loci identified by the COGENT consortium.
Early screening for colorectal cancer can be extremely helpful in identifying individuals with polyps and nonpolypoid lesions and preventing the development of cancer. Regular faecal occult blood tests (FOBT) in the over 50 s for example have been found to reduce the number of deaths due to CRC by 15–33%. In the UK, screening is offered to all men and women aged between 60 and 69 at a cost of £77.3 million and this will be extended to 74 year olds. However, it has been suggested that if individuals are provided with a personalized disease risk assessment from their combined genetic and environmental profile, they are likely to be more motivated to alter their lifestyle as a preventative measure, which would increase the effectiveness of health campaigns. In this study we develop predictions of CRC risk in different sub populations and assess the impact of modifying lifestyle factors on risk levels. By providing predictions of disease risk both before and after a lifestyle change for a given genetic profile, the study illustrates the potential benefits for both selection of candidates for screening programmes and the tailored promotion of healthier lifestyle choices, in high risk groups.
There are several modifiable risk factors for colorectal cancer and building predictive models encompassing both genetic and environmental factors enables us to move in the direction of a complete assessment of disease risk. This paper describes a predictive model which takes account of the known genetic contribution as well as the modifiable risks. There is considerable evidence to suggest that detecting polyps in the early stages can reduce mortality rates for colorectal cancer and whilst the interactions between the genetic and environmental elements are undeniably complex, separating out the inherited risk from the lifestyle factors using this model helps to illustrate the potential gains from modifying lifestyle behaviour and could usefully inform healthy lifestyle campaigns.
Our findings indicate that that cessation of alcohol consumption and reducing obesity levels lead to the most significant changes to the proportion of the population reducing their disease risk category. Whilst this could have been predicted to some extent by the higher odds ratios for these factors, it is the combination of relative risk, together with the prevalence of the factor within the population that determines the overall impact. In addition, being able to create personalized risk predictions in this way, has the potential to motivate greater behavioural change, showing for example, that it is possible to significantly reduce disease risk by moving from a high risk category to an average risk category though increasing fibre levels; cessation of alcohol consumption or weight management, given a particular genetic profile. Further research is required to increase understanding of how individuals respond to risk assessment based on genetic information. This may increases their motivation since the results are personal, or decrease their motivation because they consider that their genetic risk cannot be modified.
Our focus has been on risk categorization, and not on the absolute level of risk estimated from the combination of genetic and environmental risk factors, which is modest for most categories. There are two advantages to this strategy. Firstly it moves away from the strategy used, for example, by direct-to-consumer genetic testing companies such as 23andme and deCODEme (who provide a single figure of risk with no confidence intervals) towards the strategy deployed in genetic counselling of using a qualitative risk level, which can be more easily interpreted for the purpose of risk prediction. Secondly, it puts a stronger statistical framework on the risk model: an assignment to elevated risk implies that the risk is statistically distinct from the risk of the average, baseline, individual, given the uncertainty of the parameters used in the model.
There are several limitations of the model. Firstly, the model is built from estimates in the literature extracted from different studies. This enables researchers to select the best study to capture information on each risk factor, but assumes that information is directly comparable between studies. This limits the precision with which risk estimates can be calculated. A further limitation is that the model assumes all risk factors entered are independent. For known gene and environment interactions, this can be overcome by either modelling the interaction explicitly as an environmental risk factor, or by omitting known genetic loci to prevent over-representation of a risk factor (such as SNPs on the FTO gene which are associated with BMI). Within the genetic component, linkage disequilibrium between SNPs can be tested to confirm no correlation at a population level; few interactions of risk between genetic loci have been identified, so the assumption of independence should not be a major problem. For the environmental component, assumptions of independence are more difficult to assess. Lack of independence may lead to inaccuracies in the population frequencies estimated, but the contribution of environmental factors to the model is based on relative risks that are estimated in the presence of relevant covariates, so levels of risk should not be inflated. Increasing our understanding of the association between lifestyle factors, as well as between genes and the environment, will be important in obtaining more accurate assessments of risk. In addition, the accuracy could be further improved by more specific modelling of the population being targeted. Applying data with relative risks by sex, by population group, or for individuals with a first degree relative with CRC for example, would provide more accurate estimations of disease risk specific to those populations.
Colorectal cancer screening programmes are widespread, but are age-targeted and look for signs of cancer in early development. In contrast, the methods described here can be used to target lifestyle factors, and are relevant for younger age-groups. The approach could encourage behavioural changes and help to reduce CRC rates. Although the model indicates that certain individuals can reduce their CRC risk by changing their behaviour, the time taken for changes in environmental risk factors to have an effect on risk is unknown, and will differ by factor. Additional research is needed to further elucidate the genetic and environmental contributions to disease risk and to measure the longer term impact of behavioural change on disease outcomes.
This information sheet is available in pdf form by clicking this link Variants of Uncertain Significance
Lynch Syndrome is a genetic condition that carries a high risk of colorectal (bowel) cancer and other cancers. Individuals at risk for Lynch Syndrome can have genetic testing for it. The test may confirm a diagnosis and determine actions that can be taken. Results from genetic testing can also affect the perspectives of relatives who might also be affected.
What is a VUS? A variant of uncertain significance (VUS) is a genetic sequence change whose association with disease risk is currently unknown.
Most genetic test results are either ‘positive for a deleterious mutation,’ or ‘no mutation detected.’ However, as in many areas of medicine, results are occasionally inconclusive; consequently, medical management decisions are based on other contributing factors.
In the field of cancer genetics, clinicians and patients have encountered challenges related to the significance of unclassified genetic variants (UV) or variants of unknown significance (VUS). VUS are data that may not provide enough information to make decisions. As the field of medical genetics moves toward whole genome sequencing (WGS), these challenges will inevitably become more frequent. VUS represent ambiguous and uncertain data, for which pathogenicity has not been demonstrated or excluded in published literature, mutation databases or on the basis of other clinical findings. Such variants present a clinical interpretation challenge and also evoke new counseling dilemmas for the understanding and psychosocial impact of uncertain genetic test results.
How do I manage a patient with a VUS? Since it is not possible to classify the genetic change as deleterious or benign, the patient should be managed based on personal and family history.
Individualized management may include increased surveillance and possibly other interventions, such as surgery or chemoprevention. Consider reviewing the case with your specialist to discuss appropriate management in the context of the specific patient and family history, and to explore whether additional work-up is indicated for the patient or family.
In practice, patients may be screened as usual for Lynch Syndrome if the clinical history was suggestive of this, but we would currently be unable to offer presymptomatic genetics testing to unaffected relatives, unless the variant was reclassified as a probable pathogenic mutation.
|Result||No mutation detected (about 90% of results)||Variant, favor polymorphism (rare)||Genetic Variant of Uncertain Significance (rare)||Variant, suspected deleterious (rare)|
|Negative||Almost certainly negative||Inconclusive||Almost certainly positive||Positive|
|Cause of cancer in family has not been determined; patient may have increased cancer risk, but hereditary cancer less likely||Cause of cancer in family not likely due to this variant; patient may have increased cancer risk, but hereditary cancer less likely||May turn out to be positive or negative; physician will be notified once reclassified||Patient likely has the syndrome with cancer risks defined by the syndrome||Patient is confirmed to have the syndrome; cancer risks defined by the syndrome|
|Manage based on personal and family history||Manage based on personal and family history||Manage based on personal and family history; provider should receive invitation for patient to participate in Variant Classification Program||Manage according to guidelines for syndrome; suggest single site testing for family members||Manage according to guidelines for syndrome; suggest single site testing for family members|
|What happens once a variant is reclassified?
Over time, a variant will often get reclassified as either a benign polymorphism or a deleterious mutation. When this occurs, an amended report is sent to the original ordering provider. While most clinical genetics centres proactively reclassify variants and communicates new findings to the original ordering providers, it is important to urge your patients with VUSs to keep in contact with your office or to notify the laboratory of an alternative provider if they move, so that they and their family can benefit from new information as it becomes available.
Cancer Research UK-funded scientists have discovered that two gene faults increase the risk of bowel cancer in families with a strong history of developing the disease, who, until now, had no explanation as to why their risk was greater. The research is published in Nature Genetics1.
To find the faults, the researchers from the University of Oxford and The Institute of Cancer Research, London, scanned the genes of 20 people2 from families with a strong history of bowel cancer. They found everyone who had a faulty POLE or POLD1 gene developed bowel cancer or had a precancerous growth in the bowel.
The two genes are so-called ‘dominant’ genes, where only one faulty copy needs to be inherited for someone to be at a high risk of developing bowel cancer.
To confirm their findings they then looked for the faults in almost 4,000 people with bowel cancer and 6,700 without the disease. Neither of the faults were found in people without bowel cancer, while 12 people with the POLE gene were found in the bowel cancer group and one person had a POLD1 gene fault.
The POLD1 fault was also found to increase the risk of getting womb cancer and possibly brain tumours with seven people in the study being diagnosed with womb cancer and one developing two brain tumours.
Cancer Research UK’s Professor Ian Tomlinson, lead researcher based at the University of Oxford, said: “There are some families where large numbers of relatives develop bowel cancer but who don’t have any of the known gene faults that raise the risk of developing the disease.
“These two faults are rare, but if you inherit them your chance of bowel cancer is high. By testing people with a strong family history of the disease for these faults, we can identify those who are at high risk and try to prevent the disease by using colonoscopy and other methods.”
POLE and POLD1 are involved in scanning and repairing damage to DNA, removing incorrect sequences from the DNA chain. Without these genes, affected individuals build up damage in their DNA which can cause bowel cancer.
Study co-leader Professor Richard Houlston from The Institute of Cancer Research said: “Uncovering gene faults like these two is extremely important, as inherited susceptibility plays a role in the development of about a third of all cases of colorectal cancer.
“This is one of the most important discoveries in bowel cancer genetics in years. It should allow us to manage families affected by inherited bowel cancer much more effectively, and it offers new clues for the prevention or treatment of all forms of the disease.”
Joe Wiegand, a financial advisor from Hampshire, was diagnosed with bowel cancer seven and a half years ago at just 28 years old. Joe had most of his large bowel removed and six months of chemotherapy. His treatment was successful and he is now followed up once a year with a sigmoidoscopy. As many of Joe’s relatives had also had bowel cancer, during his treatment he was invited to take part in this study to investigate genetic faults that may be behind his cancer.
Joe said: “There’s a very strong history of bowel cancer in my family – my dad’s mother and sister both had it, my dad was diagnosed with it at 43 and a few cousins have had bowel cancers and brain tumours. It’s clear that something’s going on in our family. I hope that taking part in this study will spare my two children the uncertainty of not knowing if they have this gene fault by having a simple yes or no blood test.”
Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “This research provides another piece of the puzzle for families who have a much greater risk of developing bowel cancer.
“Cancer Research UK scientists have played an important role in finding the gene faults that increase cancer risk. Their work means doctors can help families with a strong family history by preventing cancer from developing or diagnosing it earlier to help more people survive.”
Palles, C et al Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas Nature Genetics (2012)